Transdermal systems containing multilayer adhesive matrices to modify drug delivery

ABSTRACT

A transdermal drug-containing dosage unit comprises: a backing layer substantially impervious to the drug to be delivered transdermally; a first polymeric adhesive matrix, in contact with the backing layer, having dispersed therein the drug and having a first delivery profile of the drug; a second polymeric adhesive matrix, in contact with said first polymeric adhesive matrix, having dispersed therein the drug and having a second delivery profile of the drug, wherein said second delivery profile is different from said first delivery profile; and a release liner in contact with the second polymeric adhesive matrix. The first polymeric adhesive matrix can release the drug more quickly or more slowly than the second polymeric adhesive matrix. Through the selection of the two matrices, the delivery profile of the drug through the skin can be selectively modified and controlled.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. patent application Ser. No.10/795,584 filed on Mar. 9, 2004 and published as U.S. Pat. Pub.2005/0202073, which is herein incorporated by reference in its entirety.This application also claims priority to PCT ApplicationPCT/US2005/005223 filed on Feb. 18, 2005 and published as WO2005/091852, which is herein incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

This invention relates to transdermal, pressure sensitive, adhesivedelivery systems for the delivery of an agent, such as a drug, throughthe skin. More specifically, this invention is directed to such systemswhich comprise multilayer adhesive matrices.

A well-known method of delivering certain drugs in a controlled mannerover time is through the use of a transdermal composition, such as apressure sensitive adhesive containing the drug. Known delivery systemsinvolve the incorporation of the desired drug into a carrier, such as apolymeric matrix and/or pressure sensitive adhesive formulation.Problems encountered with such delivery systems have includedinsufficient control over the rate and duration of the transdermalabsorption, and a variety of compositions have been developed in effortsto maximize control of the release of a desired drug and the efficacy ofthe delivery unit.

Although a number of commercially useful transdermal delivery systemshave been produced, further improvements are sought.

SUMMARY OF THE INVENTION

In accordance with the present invention, a transdermal drug-containingdosage unit comprises:

a) a backing layer substantially impervious to the drug to be deliveredtransdermally;

b) a first polymeric adhesive matrix, in contact with at least a portionof the backing layer, having dispersed therein the drug and having afirst initial delivery profile of the drug;

c) a second polymeric adhesive matrix, in contact with at least aportion of said first polymeric adhesive matrix, having dispersedtherein the drug and having a second delivery profile of the drug,wherein said second delivery profile is different from said firstdelivery profile; and

d) a removable release liner in contact with at least a portion of thesecond polymeric adhesive matrix.

The invention further comprises a method for administering a drugtransdermally to an individual in need of such administration,comprising applying to the skin of the individual a transdermal dosageunit comprising:

a) a backing layer substantially impervious to the drug to be deliveredtransdermally;

b) a first polymeric adhesive matrix, in contact with at least a portionof the backing layer, having dispersed therein the drug and having afirst initial delivery profile of the drug; and

c) a second polymeric adhesive matrix, in contact with at least aportion of said first polymeric adhesive matrix, having dispersedtherein the drug and having a second delivery profile of the drug,wherein said second delivery profile is different from said firstdelivery profile.

The first polymeric adhesive matrix can release the drug more quickly ormore slowly than the second polymeric adhesive matrix. Through theselection of the two matrices, the delivery profile of the drug throughthe skin can be selectively modified and controlled to an extent notpossible with delivery devices which comprise only a single adhesivematrix.

If desired, the compositions further can contain or employ otheringredients known for use in pressure sensitive adhesives, includingcrosslinking agents, plasticizers, tackifiers, anti-oxidants andexcipients or penetration enhancers.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph showing the transdermal flux (rate of delivery) ofthree matrices, including a bi-layer matrix in accordance with thisinvention.

FIG. 2 is a graph showing the cumulative delivery of the three matricesof FIG. 1.

FIGS. 3 a and 3 b are graphs showing cumulative delivery for slowskin-contact adhesives adhesive bi-layers (i.e., the adhesive matrixhaving the slower initial rate of drug delivery is the skin contactlayer). FIG. 3 a shows the in vitro transdermal data and FIG. 3 b showsthe polynomial correlation for a fast adhesive monolith and severalbi-layer matrices in accordance with this invention.

FIGS. 4 a and 4 b are 3-dimensional correlation graphs for slowskin-contact adhesive bi-layers. FIG. 4 a shows the 3-D cumulativedelivery correlation and FIG. 4 b shows the 3-D flux correlation forslow skin-contact adhesives bi-layers.

FIGS. 5 a and 5 b are graphs showing cumulative delivery for fastskin-contact adhesives adhesive bi-layers (i.e., the adhesive matrixhaving the faster initial rate of drug delivery is the skin contactlayer). FIG. 5 a shows the in vitro transdermal data and FIG. 5 b showsthe polynomial correlation for several bi-layer matrices in accordancewith this invention.

FIGS. 6 a and 6 b are 3-dimensional correlation graphs for fastskin-contact adhesive bi-layers. FIG. 6 a shows the 3-D cumulativedelivery correlation and FIG. 6 b shows the 3-D flux correlation forslow skin-contact adhesive bi-layers.

FIG. 7 shows the thermodynamic activity of a bi-layer system of varyinglayer thickness ratio relative to its constituent monoliths at aconstant average concentration.

DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to dermal compositions suitable for thedelivery of a drug through the skin. The compositions allow for verycontrolled delivery of the drug through the unique combination of two ormore different adhesive matrices which can be selected and layered toprovide a desired drug delivery profile.

Specifically, compositions of the present invention comprise:

a) a backing layer substantially impervious to the drug to be deliveredtransdermally;

b) a first polymeric adhesive matrix, in contact with at least a portionof the backing layer, having dispersed therein the drug and having afirst delivery profile of the drug;

c) a second polymeric adhesive matrix, in contact with a portion of saidfirst polymeric adhesive matrix, having dispersed therein the drug andhaving a second delivery profile of the drug; and

d) a removable release liner in contact with at least a portion of thesecond polymeric adhesive matrix.

The first and second polymeric adhesive matrices in a two matrixcomposition also will be referred to as the anchor adhesive layer andthe skin contact adhesive layer, respectively. They are selected suchthat there is a significant difference in the rate of drug delivery fromeach layer. In addition, the two adhesives also can be selected suchthat there is a significant difference in one or more other physicalcharacteristics, such as the solubility, miscibility or stability of thedrug or desired excipients, in each of the two layers, which can furtheraffect the delivery of the drug from the composition and through theskin of the person wearing the composition. As used herein, “significantdifference” means a difference in drug delivery of at least about10%-100%, preferably at least about 15%-60%, between the two adhesivematrices or layers. The desired difference in drug delivery ratesbetween the two layers can be achieved simply through the selection ofthe two adhesive matrices or through the selection of the adhesive foreach matrix in combination with the choice of relative thickness of eachlayer.

The first and second adhesive matrices can be selected such that therate of drug delivery initially is faster from the second matrix, orskin contact layer, than it is from the first matrix, or anchor layer.In such instances, there will be an initial burst, or spike, of drugdelivered through the skin of the wearer, followed by a slower and moresteady release of the drug. Alternatively, the adhesive matrices can beselected such that the rate of drug delivery initially is faster fromthe first matrix, or anchor layer, than it is from the second matrix, orskin contact layer. Such a system allows for the tuning of the deliveryprofile depending upon the thickness of the two layers. Specifically,the slower delivering adhesive layer contacting the skin controls thedelivery through the skin and modulates the faster delivering adhesivelayer's tendency to deliver the drug rapidly. In such instances, therewill be a continuous drug delivery, perhaps with a “burst” in deliveryat a specific time post-application, depending upon the thickness andcomposition of the matrices and the drug concentration. For instance,the burst could be accounted for by a release of drug and components bythe anchor layer having a driving force so great as to overcome any ratelimiting properties that the skin contact layer may have. Such a releasepattern is useful, for example, in delivering drugs to the body to mimica circadian rhythm (e.g., testosterone).

The rate of release from an adhesive matrix can change over the courseof its functional lifespan. Often, this is caused by the absorption ofwater or other components from the surface of the skin of the wearer.Alternatively, one can incorporate into the skin contact matrix anexhaustible penetration retardant or load the skin contact matrix withsolid drug crystals to impair initial delivery of the drug through theskin.

In one embodiment of this invention, the composition comprises more thantwo adhesive matrices, such as three or four or five adhesive matrices.For example, a composition could comprise one or more additionaladhesive matrices sandwiched in between the adhesive matrix which is incontact with the backing layer, and the adhesive matrix which is incontact with the release liner. An advantage to including three or morematrices is having increased ability to control the rate of deliveryeither through the use of the different layers or by adding differentexcipients to the different layers to change or control the rate ofdelivery. Other advantages include increased chemical stability,processing, cosmetic or physical (improved wear) advantages. If thereare more than two adhesive matrixes in a composition, the initial rateof delivery of the drug from one of the matrices is different from thatfrom at least one of the other matrices. In one embodiment, the initialrate of drug delivery in each matrix is different from that of eachother matrix.

The adhesives used in the compositions, or unit dosage forms, of thepresent invention are those which are tacky or sticky to the touch andwhich typically adhere to a substrate, such as the skin, upon theapplication of mild pressure. They therefore often are referred to aspressure sensitive adhesives.

The choice for each adhesive matrix layer can be made from any pressuresensitive adhesives conventionally used in transdermal delivery devices,provided that the two materials chosen have significantly different drugdelivery rates. In one preferred embodiment, one matrix comprises anacrylic adhesive and the other matrix comprises a silicone adhesive. Inthis combination, the acrylic adhesive has the relatively slow deliverycharacteristics; the silicone adhesive has the more rapid deliverycharacteristics. In a second preferred embodiment, one matrix comprisesan acrylic adhesive and the other comprises a polyisobutylene adhesive.In this embodiment, the acrylic adhesive again has the relatively slowdelivery characteristics; the polyisobutylene adhesive delivers the drugmore rapidly.

If the composition comprises three adhesive matrices, it can comprise,for example, an acrylic adhesive layer sandwiched between two siliconeadhesive layers, or a silicone adhesive layer in between two acrylicadhesive layers. Alternatively, each layer could have a differentpolymer, such as a silicone, polyisobutylene, and acrylate adhesivemultilayer system. The choice of adhesive for each layer will bedetermined by the delivery profile desired for the final composition.

Suitable silicone adhesives include pressure sensitive adhesives madefrom silicone polymer and resin. The polymer to resin ratio can bevaried to achieve different levels of tack. Specific examples of usefulsilicone adhesives which are commercially available include the standardBIOPSA® series (7-4400, 7-4500 and 7-4600 series) and the aminecompatible (endcapped) BIOPSA® series (7-4100, 7-4200 and 7-4300 series)manufactured by Dow Corning. Preferred adhesives include BIO-PSA®7-4202, BIO-PSA® 7-4301, BIO-PSA® 7-4302, BIO-PSA® 7-4501, BIO-PSA®7-4502 and BIO-PSA® 7-4602.

Suitable polyisobutylene adhesives are those which are pressuresensitive and have suitable tack. The polyisobutylene can comprise amixture of high and low molecular weight polyisobutylenes. Specifically,high molecular weight polyisobutylenes are those with a molecular weightof at least 1,000,000. Low molecular weight polyisobutylenes are thosewith a molecular weight of at least 100 but less than 1,000,000.Desirably, the high molecular weight polyisobutylene comprise betweenabout 20 and 80% by weight of the total polyisobutylene, preferablybetween about 40% and 50%, most preferably about 45%, and the lowmolecular weight polyisobutylene comprises between about 80% and 20% byweight of the total polyisobutylene, preferably between about 50% and60%, most preferably about 55%. A specific example of a usefulpolyisobutylene is one which comprises 45% high molecular weight polymer(˜1,250,000) and 55% low molecular weight polymer (˜44,000) atapproximately 25% solids in n-heptane.

Useful acrylic polymers include various homopolymers, copolymers,terpolymers and the like of acrylic acids. They include copolymers ofalkyl acrylates or methacrylates. Polyacrylates include acrylic acid,methacrylic acid, N-butyl acrylate, n-butyl methacrylate, hexylacrylate, 2-ethylbutyl acrylate, isooctyl acrylate, 2-ethylhexylacrylate, 2-ethylhexyl methacrylate, decyl acrylate, decylmethacrylate,dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, and tridecylmethacrylate. Useful acrylic adhesives include crosslinked carboxylfunctional adhesives such as DURO-TAK®87-2194, non-crosslinked carboxylfunctional adhesives such as DURO-TAK®87-2051, crosslinked hydroxylfunctional adhesives such as DURO-TAK®87-2516, non-crosslinked hydroxylfunctional adhesives such as DURO-TAK®87-2287, grafted adhesives such asDURO-TAK®87-5298 and non-functional adhesives such as DURO-TAK®87-4098.Preferred acrylic adhesives include crosslinked carboxyl functionalacrylic adhesives, such as DURO-TAK® 87-2194 manufactured by NationalStarch and Chemical Co.

In addition to the aforementioned adhesives, other adhesives useful incompositions in accordance with this invention include other acrylate,rubber or silicone pressure adhesives, whether hotmelt, waterborne orsolvent based.

In addition to the two or more adhesive layers, compositions inaccordance with this invention comprise a backing and a release liner,each of which can comprise materials conventionally used in transdermalpatch compositions. The material chosen for the backing is one which isflexible, impermeable to the drug, and, if desired, can be colored orlabeled. The backing provides support and a protective covering for thedosage unit. Suitable backing materials include those known in the artfor use with pressure sensitive adhesives. For example, the backing cancomprise a polyolefin, polyester, multi-layer EVA film and polyester,polyurethane or combination thereof. A preferred backing material isMEDIFLEX® 1000, a polyolefin manufactured by Mylan Technologies, Inc.

The release liner is removed and discarded from the composition toexpose the skin contact adhesive layer which functions as the means ofapplying the composition to the patient and through which the drugpasses as it is delivered to the patient. Suitable release linersinclude those known in the art for use with pressure sensitive adhesivecompositions. For example, the release liner can comprise afluorosilicone coated polyester or silicone coated polyester. Apreferred release liner is MEDIRELEASE® 2500, MEDIRELEASE® 2249 andMEDIRELEASE® MR2226, each manufactured by Mylan Technologies, Inc., orScotchpak® 1022, manufactured by 3M Pharmaceuticals/D.D.S. The releaseliner can, however, comprise other materials, including paper orpaper-containing layers or laminates, various thermoplastics, polyesterfilms, foil liners, and the like.

Once the dosage unit forms have been prepared, they are placed inappropriate packaging for storage until they are to be applied intransdermal treatment.

The compositions of this invention possess sufficient adhesiveproperties that once the release liner is removed and the composition isapplied to the skin the composition can remain in place for a period oftime sufficient to distribute the desired amount of the drug containedtherein with a low incidence of debonding.

The compositions of this invention can be made by first preparingseparate adhesive blends for each layer of the dosage unit, thendissolving or suspending the drug of choice in at least one of theblends, each of which has been made by mixing a suitable solvent withthe pressure sensitive adhesive of choice. The anchor layer is coatedfirst on a release liner, dried and then laminated to the desiredbacking film, according to predetermined parameters, such as temperatureand dwell time (line speed), which yield minimal residual solventlevels. The skin contact layer then is coated on a separate releaseliner and dried. The release liner is removed from the anchor layer andthe adhesive side of the skin contact layer is laminated onto theadhesive side of the anchor layer so that the anchor layer is betweenthe backing and the skin contact layer. If the drug initially issuspended or dissolved in only one of the two adhesive layers, it will,over time, equilibrate into the other adhesive layer until a commonequilibrium is achieved. It may be desirable to prepare the compositionwith the drug initially suspended or dispersed in only one of the twoadhesive layers if, for example, the other adhesive layer is preparedwith a solvent which would be deleterious to the drug but whichevaporates during processing (coating and drying).

If more than two layers are to be provided, the third (middle) layer iscoated as a liquid onto a release liner, dried, laminated to either theadhesive side of the dried skin contact layer or the adhesive side ofthe dried anchor layer once the release liner has been removed from thelatter, then the two parts of the dosage unit are laminated to oneanother as above.

Suitable solvents for use in preparing the adhesive blends includeacetone, heptane, ethyl acetate, isopropanol, ethanol, hexane, toluene,xylene, 2,4-pentanedione, methanol and water.

Alternative methods for producing or achieving a transdermal deliverydosage unit in accordance with this invention may be apparent to personsskilled in the art, and such alternative methods also fall within thescope of the present invention. For example, an adhesive blend can becoated onto the backing film rather than the release liner.Alternatively, an adhesive coating can be created without using asolvent, such by heating the adhesive to its melting temperature(hot-melt adhesive). With this technique, no drying of the adhesive isrequired, only cooling.

There are many coating techniques for applying a continuous liquidcoating onto a substrate, including using a gravure roll, reverse roll,falling film, inkjet, etc. All of these are well-known to persons ofordinary skill in the art and can be used to create pressure-sensitiveadhesive layers from a solvated blend. Alternatively, a thin adhesivecoating can be achieved by extrusion, in which the adhesive blend isforced through a die under pressure onto the substrate either as acontinuous coating or as a printed (intermittent) pattern.

The thickness of the anchor and skin contact layers of the compositionsof this invention can vary, depending upon such factors as the amount ofdrug to be delivered from the composition and the desired wear period.Generally, however, the skin contact layer has a thickness of betweenabout 5 and 150 gsm, preferably between about 25 and 50 gsm. The anchorlayer generally has a thickness of between about 5 and 150 gsm,preferably between about 25 and 100 gsm. Variations can be determined asa matter of routine experimentation by those of ordinary skill in theart.

The compositions of the present invention are suitable for thetransdermal delivery of a wide range of drugs. The term “drugs” isintended to have its broadest interpretation as including anytherapeutically, prophylactically and/or pharmacologically orphysiologically beneficial active substance, or a mixture thereof, whichis delivered to a living being to produce a desired, beneficial effect.More specifically, any drug which can produce a pharmacologicalresponse, localized or systemic, whether therapeutic, diagnostic, orprophylactic in nature, is within the contemplation of the presentinvention. Also included within the scope of the invention are bioactiveagents, such as insect repellants, sun screens, cosmetic agents, etc.The drug can be provided in an amount sufficient to cure, diagnose, ortreat a disease or other condition. This definition includes, but is notlimited to:

1. cardiovascular drugs, such as nitroglycerin, propranolol, isosorbidedinitrate, isosorbide mononitrates, diltiazem, nifedipine, procainamide,clonidine and others,

2. androgenic steroids, such as testosterone, methyltestosterone andfluoxymesterone,

3. estrogens, such as conjugated estrogens, esterified estrogens,etropipate, 17-β estradiol, 17-β estradiol valerate, equilin, mestranol,estrone, estriol and diethylstilbestrol,

4. progestational agents, such as progesterone, 19-norprogesterone,norethindrone, norethindrone acetate, melengestrol chloradinone,ethisterone, medroxyprogesterone acetate, hydroxyprogesterone caproate,norethynodrel, dimethisterone, ethinylestrenol, norgestrel,megestrolacetate, and ethinodiol diacetate,

5. drugs which act on the central nervous system, including sedatives,hypnotics, analgesics, anesthetics, and antianxiety agents; such assalicylic acid derivatives, opiates, opioids and the like; includingchloral hydrate, benzodiazepines, naloxone, haloperidol, pentobarbitol,phenobarbitol, secobarbital, codeine, lidocaine, dibucaine, benzocaine,fentanyl, fentanyl analogs and nicotine,

6. nutritional agents, including vitamins, essential amino acids andessential fats,

7. anti-inflammatory agents, including hydrocortisone, cortisone,dexamethasone, prednisolone, prednisone, halcinonide,methylprednisolone, flurocortisone, corticosterone, paramethasone,ibuprofen, naproxen, fenoprofen, fenbufen, indoprofen, salicylic acid,methyl salicylate, sulindac, mefenamic acid, piroxicam, indonisilone andtolmetin,

8. antihistamines, such as diphenhydramine, triprolidine,chlorcyclizine, promethazine, cyclizine, chlorprenaline, terrenadine,phenylpropanolamine and chlorpheniramine,

9. miotics, such as pilocarpine,

10. dermatological agents, such as vitamins A and E,

11. anti-spamodics, including atropine, methantheline, papverine,cinnmedrine and methscopolamine,

12. anti-depressants, such as isocaboxazid, phenelzine, imipramine,amitrptyline, trimepramine, dozepin, desipramine, nortriptyline,protriptyline, amoxapine and maprotiline,

13. anti-cancer drugs,

14. anti-diabetics, such as insulin,

15. anti-estrogens or hormone agents, including tamoxifen or HCG,

16. anti-infectives, including antibiotics, anti-bacterials andanti-virals, such as tetracycline, chloramphenicol, sulfacetamide,sulfadiazine, sulfamerazine, sulfoxazole, idoxuridine, and erythromycin,

17. anti-allergenics, such as antazoline, metapyrilene, and pyrilamine,

18. anti-pyretics, including aspirin and salicylamide,

19. anti-migraine agents, including dihydroergotamine and pizotyline,

20. tranquilizers, including reserpine, chlorpromazine, and antianxietybenzodiazepines, and

21. anti-psychotic agents, including haloperidol loxapine, molindone,thiothixene, pimozide, risperidone, quetiapine fumarate, olanzapine,and/phenothiazine derivatives.

Other drugs suitable for delivery using a transdermal system can bereadily determined by persons of ordinary skill in the art. In addition,pharmacologically acceptable derivatives of the drugs, such as ethers,esters, amides, acetals, salts and the like, which are suitable fortransdermal administration can be used.

In a preferred embodiment, a composition of this invention comprisesestradiol, a combination of estradiol and norethindrone acetate or acombination of estradiol and levonorgestrel or other progestin. Suchpatches are indicated for post-menopausal women as hormone replacementtherapy. One or more bioactive and biocompatible derivatives ofestradiol capable of being absorbed transdermally can be used in placeof, or in combination with, estradiol. Derivatives of estradiol include13- or 7-mono-esters and di-esters of estradiol, includingestradiol-3,17-diacetate; estradiol-17-acetate; estradiol-3,17-valerate;estradiol-3-valerate; estradiol-17-valerate; 3-mono-17-mono- and3,17-dipilivate esters; 3-mono-, 17-mono-, and 3,17-dipropionate esters;corresponding heptanoate and benzoate esters; ethanol estradiol;estrone; and other estrogenic steroids and derivatives which aretransdermally absorbable.

Other suitable progestins include progesterone, medroxyprogesteroneacetate, ethynodiol diacetate, and the like.

When estradiol is used as the sole active drug in the dosage unit, eachunit typically comprises from about 0.1% to about 4.0% (w/w) estradiol.When estradiol is provided in combination with either norethindrone orlevonorgestrel or other progestin, each dosage unit typically comprisesabout 0.1% to about 4.0% (w/w) estradiol and about 0.1% to about 20% ofthe progestin. These ranges are intended only as guidelines; the actualamount of drug provided depends upon the choice of adhesive for the skincontact and anchor layers, the amount of drug desired to be deliveredtransdermally to the patient within a certain period of time, and therate at which the drug can permeate through the skin of the personwearing the dosage unit or patch.

In one specific embodiment of this invention, a transdermal dosage unitcomprises a silicone skin contact layer of about 25 gsm (grams/m²) andan acrylate anchor layer of about 75 gsm and contains about 1.4% (w/w)estradiol. In a second specific embodiment, a transdermal dosage unitcomprises a silicone skin contact layer of about 50 gsm and an acrylateanchor layer of about 75 gsm and contains about 1.4% estradiol. In athird specific embodiment, a transdermal dosage unit comprises asilicone skin contact layer of about 25 gsm and an acrylate anchor layerof about 100 gsm, each containing about 1.4% estradiol.

In a fourth specific embodiment, a transdermal dosage unit comprises apolyisobutylene skin contact layer of about 50 gsm which contains 1.0%(w/w) estradiol and a 50 gsm anchor layer which contains about 1.4%(w/w) estradiol in an acrylate adhesive.

The amount of drug to be incorporated into the compositions of thisinvention vary, depending upon the drug or combination of drugs ofinterest, the desired therapeutic effect and the time span over whichthe composition will release the drug and provide therapy. As thepassage of drugs through the skin often is the rate limiting step, theamount of drug chosen and the rate of release from the adhesivestypically are selected so as to provide for delivery of the drug for aprolonged period of time, wherein the minimum amount of the drug in thesystem is based upon the rate at which it will pass through the skin inthe time period for which the composition is to provide therapy. Theamount of drug in the composition typically can vary from about 0.05% toabout 40% by weight of the delivery device and preferably is within therange of about 0.1% to about 20% by weight, most preferably within therange of about 0.1% to about 4.0% by weight.

The drug(s) of interest can be provided in admixture with otheringredients which are compatible with the transdermal administration ofthe desired drug to patients. Such other ingredients includecrosslinking agents, plasticizers, tackifiers, fillers, anti-oxidants,dispersing agents and excipients, such as propylene glycol.

The present invention provides the ability to tune the transdermaldelivery profile (e.g., maximum flux vs. average flux) by altering layerthicknesses and without risking drug crystallization. Placing the twomatrices in intimate contact at a common interface allows the drug ineither matrix to equilibrate across that interface until the drug is atthe same activity everywhere in the matrices. In one embodiment, thefull surface area of the two matrices are in contact with each other. Inanother embodiment, at least 75% of the surface area both of thematrices are in contact with each other.

In one preferred embodiment, each monolith layer comprises aconcentration of drug that is sub-saturated. Thus, any combination ofthese monoliths will be sub-saturated. While the equilibriumconcentration of the drug in the two matrices depends on the ratio oflayer thickness, the bi-layer system will always be at or belowsaturation. Thus, since each layer is sub-saturated and the layers arein equilibrium with each other, all layer-thickness combinations aresub-saturated. Therefore, the layer-thickness ratio can be selected toprovide the desired transdermal delivery profile without exceedingsolubility.

The ability to form devices that does not exceed solubility in any ofthe layers is particularly relevant in this aspect of the inventionsince this prevents the drug from recrystallizing in the matrix andminimizes stability concerns. Recrystallized drugs will generallycomprise particles having a different size and shape compared to thenon-recrystallized drug. These recrystallized drug particles will causethe composition of the invention to have a different and oftennon-preferred release profile. Further, recrystallization often occursmore readily at the surface of the matrix as solvent evaporates,creating a higher concentration of recrystallized drug at the surface ofthe adhesive and limiting the tackiness of the device and can alsoaffect delivery. One additional advantage of the compositions where eachof the layers are sub-saturated with drug is that devices with variousthicknesses and thus various activities of the drug can be formedwithout being concerned about the stability of the composition.

Thus, in one specific embodiment, the composition of the inventioncontains a drug which is sub-saturated in each layer.

In one specific embodiment, the composition has a slow skin-contactadhesive (i.e., in the bilayer system, the adhesive matrix having theslower initial rate of drug delivery is the skin contact layer and theadhesive matrix having the faster initial rate of drug delivery is theanchor layer) and the cumulative delivery of a drug is substantiallylinear over the delivery time, such as depicted by the bi-layer devicesin FIG. 3 a.

In one specific embodiment, the composition has a fast skin-contactadhesive (i.e., in the bilayer system, the adhesive matrix having thefaster initial rate of drug delivery is the skin contact layer) and thedrug flux rate comprises a delivery spike and then a steady-state flux.In one embodiment, the delivery spike has an intensity of at least 1.2times the steady-state flux. In one embodiment, the delivery spike hasan intensity of at least 1.5 times the steady-state flux.

The invention is further illustrated by the following examples, whichare not to be construed as limiting.

EXAMPLES Example 1 Preparation of a Two-Layer Delivery Device

Separate adhesive blends are made for each layer of the finished system,with the drug dissolved or suspended in at least one blend. The blendsare made by suspending or dissolving the drug in a combination ofsolvent, adhesive, and, optionally, excipient. Desired remainingcomponents for each blend can be dispersed in a premix or added directlyto the adhesive blends along with the drug. Once all the components areadded together in their respective blend, the blends are mixedseparately with an air driven mixer until uniform. See Table 1 below forexample amounts of each component blend:

TABLE 1 Component % (w/w) Wet Weight (g) Anchor Layer Blend EthylAlcohol Dehydrated 4.56 9.50 Alcohol USP-200 Proof punctilious (EthylAlcohol) Estradiol Hemihydrate, USP, micronized 0.63 1.32 Povidone USP(Plasdone K-29/32) 1.55 3.23 DURO-TAK ® 87-2194 93.25 194.14 SkinContact Layer Blend Ethyl Alcohol Dehydrated 5.89 6.00 Alcohol USP-200Proof punctilious (Ethyl Alcohol) Estradiol Hemihydrate, USP, micronized0.81 0.83 Povidone USP (Plasdone K-29/32) 2.00 2.04 360 Medical Fluid(100 cSt.) 2.94 3.00 BIO-PSA ®7-4502 88.36 90.08

Following thorough mixing, the anchor layer blend is coated onto anappropriate release liner at the specified thickness to obtain thedesired gsm. The laminate is dried for 4 minutes at 41° C. followed by 4minutes at 77° C. in forced air ovens, then laminated to the desiredbacking film. The skin contact layer blend is coated onto a separaterelease liner and dried, using the same conditions as were used toprepare the anchor layer laminate.

To assemble the finished product, the anchor layer release liner isremoved and the adhesive side of the dried skin contact layer islaminated to the adhesive side of the anchor layer.

Example 2

Transdermal delivery devices were made in accordance with the teachingsof Example 1. Each device contained a total of 0.1-4.0% (w/w) drug. Theanchor adhesive matrix of each delivery device was an acrylicpressure-sensitive adhesive and initially contained 0.1%-4.0% drug andbetween 0-5.0% (w/w) povidone. The skin contact matrix of each deliverydevice comprised a silicone pressure-sensitive adhesive and initiallycontained 0.1% to 4.0% of the drug, 0-5% (w/w) povidone and 0-5% of atackifier/plasticizer. The silicone contact layer of each device had athickness of 5-100 gsm and the anchor layer had a thickness of 5-150gsm. In one embodiment, the device comprised 1.4% estradiol in each ofthe acrylic adhesive layer and the skin contact layer, 3.4% povidone ineach of the acrylic adhesive layer and the skin contact layer, and theskin contact layer comprised 5% of 360 Medical Fluid (100 cSt) as thetackifier/plasticizer.

Example 3

Transdermal delivery devices were made in accordance with the teachingsof Example 1. Each device contained a total of 0.1-4.0% (w/w) drug. Theanchor adhesive matrix of each delivery device was an acrylicpressure-sensitive adhesive and initially contained 1.4% drug andbetween 0-5.0% (w/w) povidone. The anchor layer also contained 0-10%(w/w) propylene glycol. The skin contact matrix of each delivery devicecomprised a polyisobutylene pressure-sensitive adhesive and initiallycontained 1.0% drug, 0-5% (w/w) povidone and 10-50% of atackifies/plasticizer. In each device, the skin contact layer had athickness of 5-100 gsm and the anchor layer had a thickness of 5-100gsm. In one embodiment, the device comprised 3.4% povidone in each ofthe acrylic adhesive layer and the skin contact layer, and the skincontact layer comprised 30% mineral oil as the tackifier/plasticizer.

Example 4

A transdermal device was made in accordance with the teachings ofExample 2. The silicone skin contact layer had a thickness of 25 gsm andthe anchor layer had a thickness of 75 gsm.

Example 5

A transdermal device was made in accordance with the teachings ofExample 2. The silicone skin contact layer had a thickness of 50 gsm andthe anchor layer had a thickness of 75 gsm.

Example 6

A transdermal delivery device was made in accordance with the teachingsof Example 3. The polyisobutylene skin contact layer had a thickness of50 gsm and the acrylate anchor layer had a thickness of 50 gsm.

Example 7

Transdermal delivery devices were made in accordance with the teachingsof each of Examples 2 and 3. In each device, the drug was estradiol, acombination of estradiol and norethindrone acetate or a combination ofestradiol and levonorgestrel.

Example 8

Transdermal delivery devices were made in accordance with the teachingsof Example 2. In each device, the silicon adhesive was BIO-PSA® 7-4202,7-4301, 7-4302, 7-4501, 7-4502 or 7-4602.

Example 9

Transdermal delivery devices were made in accordance with the teachingsof Example 3. In each device, the polyisobutylene adhesive comprisedfrom 20-80% of polyisobutylene with a molecular weight of at least1,000,000 and 80-20% of polyisobutylene with a molecular weight ofbetween 100 and 1,000,000.

Example 10

Transdermal delivery devices were made in accordance with the teachingsof Example 9. In each device, the polyisobutylene adhesive comprised 45%polyisobutylene with a molecular weight of at least 1,000,000 and 55%polyisobutylene with a molecular weight of between 100 and 1,000,000.

Example 11

A transdermal delivery device was made in accordance with the teachingsof Example 2. The 50 gsm skin contact layer contained 1.4% estradiolhemihydrate, 3.4% povidone and 5% 360 Medical Fluid (100 cSt) in amedical grade, silicone pressure sensitive adhesive BIO-PSA® 7-4502. The75 gsm anchor layer contained 1.4% estradiol hemihydrate and 3.4%povidone in DURO-TAK® 87-2194, a medical grade acrylate pressuresensitive adhesive. The backing consisted of polyolefin (MEDIFLEX®1000). The release liner was fluorosilicone coated polyester(MEDIRELEASE® 2500 or Scotchpak® 1022). All percentages are w/w.

The delivery system had a size of 30 cm², produced a delivery spike ofestradiol and delivered approximately 0.1 mg/day in vitro.

Example 12

A transdermal delivery device was made in accordance with the teachingsof Example 3. The 50 gsm skin contact layer contained 1.0% estradiolhemihydrate, 3.4% povidone and 30% mineral oil in medical gradepolyisobutylene pressure sensitive adhesive. The 50 gsm anchor layercontained 1.37% estradiol hemihydrate, 8.0% propylene glycol and 3.4%povidone in DURO-TAK® 87-2194, a medical grade acrylate pressuresensitive adhesive. The backing consisted of polyolefin (MEDIFLEX®1000). The release liner was siliconized polyester (MEDIRELEASE® 2249).All percentages are given on a w/w basis.

The delivery device had a size of 30 cm², produced a delivery spike ofestradiol and delivered 0.1 mg/day in vitro.

Example 13

A transdermal delivery device was made in accordance with the teachingsof Example 1. The anchor layer matrix comprised 50 gsm DURO-TAK® 87-2194to which was laminated a 50 gsm polyisobutylene skin contact layermatrix. The anchor layer matrix contained 1.37% estradiol hemihydrate,4.0% propylene glycol, 3.4% povidone and 1.13% colloidal silicondioxide. The skin contact layer matrix contained 1.37% estradiolhemihydrate, 3.4% povidone, 4.0% propylene glycol, 1.13% colloidalsilicon dioxide, and 30% mineral oil in a polyisobutylene adhesive. Thebacking was MEDIFLEX® 1000 and the release liner was MEDIRELEASE® 2226.

Example 14

A transdermal delivery device was made in accordance with the teachingsof Example 1. The anchor layer matrix comprised 75 gsm DURO-TAK® 87-2194to which was laminated a 50 gsm skin contact layer matrix of BIO-PSA®7-4502. The anchor layer matrix contained 1.37% estradiol hemihydrateand 3.4% povidone. The skin contact layer matrix contained 1.37%estradiol hemihydrate, 3.4% povidone and 5% 360 Medical Fluid (100 cSt).The backing was MEDIFLEX® 1000 and the release liner was MEDIRELEASE®2500.

Example 15

A delivery device was made in which the rate of delivery of drug fromthe skin contact layer was slower than the rate of release from theanchor layer. The transdermal delivery profiles of the bilayer andconstitutive monolayers show that the bi-layer delivers drug through theskin at the same normalized rate as the rapidly delivering (silicone)matrix, but at a steady rate characteristic of the slow-delivery(acrylic) matrix.

Rapidly delivering adhesive films were prepared by coating a siliconeadhesive blend so as to create a homogeneous dry adhesive layercontaining 1.25% estradiol, 5% polyvinyl pyrrolidone, 4% oleic acid, andBIO-PSA® 7-4502 silicone adhesive. The blend was coated onto 3MScotchPak® 1022 release liner and dried for 4 minutes at 41° C. and 4minutes at 77° C. to create adhesive films of approximately 100 gramsper square meter (gsm).

Slowly delivering adhesive films were prepared by coating an acrylicadhesive blend so as to create a homogeneous dry adhesive layercontaining 1.25% estradiol, 5% polyvinyl pyrolidone, 4% oleic acid andDURO-TAK® 87-2516 acrylic adhesive from National Starch and Chemical Co.The blend was coated onto MEDIRELEASE® 2249 release liner and dried for4 minutes at 40° C. and 4 minutes at 77° C. to create two dry adhesivefilms of approximately 25 and 100 gsm, respectively.

Two drug delivery systems were prepared by laminating either the 100 gsmrapidly delivering silicone adhesive film or the 100 gsm slowlydelivering acrylic adhesive film to 3M CoTran 9722 backing film.

A third drug delivery system was prepared by first transferring therapidly delivering silicone adhesive film from the release liner to 3MCoTran 9722 backing film. The 25 gsm slowly delivering acrylic adhesivefilm was laminated on top of the rapidly delivering silicone adhesivefilm. The finished system consisted of a backing film, 100 gsm siliconeadhesive layer, 25 gsm acrylic adhesive layer and release liner. Afterallowing all systems to equilibrate, they were tested for in vitrodelivery of drug through human skin. The table below summarizes thethree systems tested:

System 3 (Bi- Layer with Slowly System 1 (Rapidly System 2 (SlowlyDelivering Acrylic Delivering Silicone Delivering Acrylic Matrix inContact Adhesive Matrix) Matrix) with Skin) GSM: 100 GSM: 100 AcrylicGSM: 25 Silicone GSM: 100 Estradiol 1.25% Estradiol 1.25% Estradiol1.25% PVP 5% PVP 5% PVP 5% Oleic Acid 4% Oleic Acid 4% Oleic Acid 4%

By laminating the two layers together, the resulting transdermal systemdelivered the medication through the skin at the same normalized rate asthe rapidly-delivering matrix, but at a steady continuous rate morecharacteristic of the slowly-delivering matrix. See FIGS. 1 and 2.

Example 16

Bi-layer transdermal devices were made in accordance with the teachingsof Example 1. Devices using a slower adhesive as the skin-contact layerand the faster adhesive as the anchor layer (the slow skin-contactadhesive bi-layer) as well as devices using the faster adhesive as theskin-contact layer and the slower adhesive as the anchor layer (the fastskin-contact adhesive bi-layer) were made. For comparison, single layer(monolithic) transdermal devices were also made in accordance with thisteaching.

The drug delivery devices were adhered to the stratum corneum ofheat-split human cadaver epidermis and mounted in a horizontal diffusionchamber. The devices used in this study had a 2 cm² diffusion area andat least three replicates were performed for each formulation/donorcombination. The temperature of the receptor solution was kept at 32° C.with constant stirring. The receptor solution (normal saline with 0.015%NaN₃) was collected and analyzed for drug concentration by HPLC atpredetermined intervals to calculate the cumulative amount of drugdelivered at each time point and the average flux between time points.

FIGS. 3 a and 3 b provide the results for devices having a slow-skincontact adhesive. Using the slower adhesive as the skin-contact layerlimits the delivery spike associated with a monolith made from a fasterdelivering adhesive. Varying the thickness ratio between the two layersbetween 10% and 50% allowed tuning of the delivery spike relative to thesteady-state flux. FIGS. 4 a and 4 b provide a three-dimensional view ofboth the cumulative delivery and flux for the fast adhesive and the fastadhesive anchor layer having up to 50% slow skin-contact adhesive. Theslow skin-contact adhesive spreads out the flux spike characteristic ofthe faster adhesive resulting in a higher steady-state flux than eitheradhesive can achieve as a monolith.

FIGS. 5 a and 5 b provide the results for devices having a fast skincontact adhesive. Using a faster adhesive as the skin-contact layercreates a variable delivery spike without sacrificing the long-termsteady-state delivery associated with a monolith made from a slowerdelivering adhesive. Varying the thickness ratio between the two layersbetween 10% and 50% allows tuning of the delivery spike while retainingthe long-term steady-state flux associated with the slower adhesive.FIGS. 6 a and 6 b provide a three-dimensional view of both thecumulative delivery and flux for the slow adhesive and for the slowadhesive anchor layer with up to 50% fast skin-contact adhesive. Thefast skin-contact adhesive creates a variable bolus or priming dosefollowed by the long-term steady-state flux characteristic of the sloweradhesive.

FIG. 7 demonstrates the linear relationship of the total activity of theadhesives in the monolith as the relative amount of each adhesive in thedevices is changed at constant average concentration.

The invention claimed is:
 1. A method for making a transdermaldrug-containing dosage unit which comprises a laminate comprising:contacting a backing layer substantially impervious to a drug to bedelivered transdermally; with a first polymeric adhesive matrix, havingdispersed therein a drug and having a first initial rate of delivery ofthe drug; contacting the first polymeric adhesive matrix with a secondpolymeric adhesive matrix, having dispersed therein the drug and havinga second initial rate of delivery of the drug, wherein said secondinitial rate of delivery is different from said first initial rate ofdelivery; and contacting the second polymeric adhesive matrix with arelease liner.
 2. The method of claim 1, wherein said first polymericadhesive matrix delivers said drug more slowly than said secondpolymeric adhesive matrix.
 3. The method claim 1, wherein said secondpolymeric adhesive matrix delivers said drug more slowly than said firstpolymeric adhesive matrix.
 4. The method of claim 1, wherein one of saidfirst and second adhesive matrices has an initial delivery rate of agiven amount of said drug that is at least about 10% faster than that ofthe other of said adhesive matrices.
 5. The method of claim 1, whereineither said first or said second polymeric adhesive matrix comprises anacrylic adhesive.
 6. The method of claim 1, wherein said first adhesivematrix comprises an acrylic adhesive and said second adhesive matrixcomprises a silicone adhesive.
 7. The method of claim 1, wherein saidfirst adhesive matrix comprises an acrylic adhesive and said secondadhesive matrix comprises a polyisobutylene adhesive.
 8. The method ofclaim 6, wherein said silicone adhesive comprises a standard siliconeadhesive or an amine compatible silicone adhesive.
 9. A method formaking a transdermal drug-containing dosage unit which comprises alaminate comprising: contacting a backing layer substantially imperviousto the drug to be delivered transdermally with a first polymericadhesive matrix, having dispersed therein a drug and having a firstinitial rate of delivery of the drug; contacting a second polymericadhesive matrix, having dispersed therein the drug and having a secondinitial rate of delivery of the drug with the first adhesive matrix;contacting a third polymeric adhesive matrix, having dispersed thereinthe drug and having a third initial rate of delivery of the drug withthe second adhesive matrix; and contacting a release liner with thethird polymeric adhesive matrix; wherein said initial rates of deliveryof at least two of said matrices are different from one another.
 10. Themethod of claim 9, which further comprises contacting at least oneadditional drug-containing polymeric adhesive matrix with said first andsecond polymeric adhesive matrices.
 11. The method of claim 9, whereineach of said first, second and third initial rates of delivery isdifferent from said other initial rates of delivery.
 12. The method ofclaim 9, wherein either said first and third adhesive matrices or saidsecond adhesive matrix comprises an acrylic adhesive.
 13. The method ofclaim 1, wherein said drug comprises a cardiovascular drug, anandrogenic steroid, an estrogen, a progestational agent, a drug whichacts on the central nervous system, a nutritional agent, ananti-inflammatory agent, an antihistamine, a miotic, a dermatologicalagent, an anti-spasmodic, an anti-depressant, an anti-cancer drug, ananti-diabetic, an anti-estrogen, an anti-psychotic, an anti-infectiveagent, an anti-allergenic, an anti-pyretic, an anti-migraine agent or atranquilizer.
 14. The method of claim 1, wherein said drug comprises anestrogen or a combination of an estrogen and a progestin.
 15. The methodof claim 14, wherein said estrogen comprises estradiol or mono- ordi-esters thereof which are transdermally absorbable.
 16. The method ofclaim 14 wherein said progestin comprises norethindrone acetate orlevonorgestrel.
 17. The method of claim 1 wherein the transdermaldrug-containing dosage unit comprises from about 0.1% to about 4.0% w/wof the drug.
 18. The method of claim 14 wherein the transdermaldrug-containing dosage unit comprises from about 0.1% to about 4.0% ofsaid estrogen.
 19. The method of claim 18 wherein the transdermaldrug-containing dosage unit further comprises from about 0.1% to about20% of the progestin.